Neurotropic drug and method for preparation of same

ABSTRACT

A new chemical compound, ketopantoyl aminobutyrate of formula I: ##STR1## and its salts. The compound is obtained by interaction of ketopantolactone and a salt of γ-aminobutyric acid. 
     It was shown that the new compound exhibits sedative, anti-amnesic and antihypoxic properties.

TECHNICAL FIELD

The invention relates to the field of medicine, more specifically to thepharmaceutical field, in particular, to a new neurotropic drug whichaffects the central nervous system and may be used in neurology,psychiatry, including in the treatment of Alzheimer' diseases

BACKGROUND

The invention concerns new derivatives of γ-aminobutyric acid. Thisacid, known as a preparation under the name of aminalon (gammalon),exhibits neurotropic activity and is used in the practice of medicine.However, it does have a number of disadvantages, such as a low activitylevel, side effects and a narrow spectrum of action which limits itsapplications.

Of the various derivatives of the γ-aminobutyric acid currently in useas neurotropic agents, calcium salt of the D-homopantothenic acid, knownunder the commercial name of "pantogam", is most closely related to theagents of the present invention. (M. D. Mashkovsky, PharmaceuticalDrugs, Moscow, Meditsina, 1986, vol. 1, page 624; Y. Nishizawa, Studieson homopantothenic acid, Medical Journal, Osaka, University, 1984, vol.35, No. 1,2, pp. 41-50). Pantogam, when compared to aminalon, hassuperior properties due to better penetration of the hematoencephaliticbarrier, which results in higher effectiveness and a wider range ofaction, at the same time exhibiting sedative and other neurotropicproperties. (T. A. Voronina, T. L. Garibova, I. V. Khromova, U. M.Tilekeeva, Dissociation of Anti-amnesic and Antihypoxic Effects ofNootropic and Antihypoxic Drugs, Pharmacology and Toxicology, 1987, No.3, pp. 21-24).

However, this drug also has several disadvantages. A therapeutic effectis achieved only by administration of a high dose of the drug, up to 3grams a day. Consequently, it has a very low therapeutic index (3.3),and may sometimes have undesirable side effects, such as depression andmyorelaxation.

Furthermore, one of the components of pantogam is the expensiveD-pantolactone, which is derived by the separation of the syntheticDL-pantolactone into enantiomers. This multi-stage process involvesdifficult-to-obtain, toxic and flammable substances and solvents, andresults in a considerable amount of waste.

DISCLOSURE OF THE INVENTION

To overcome the disadvantages of the known neurotropic agents, it is theobject of this invention to create an effective drug suitable for abroad range of applications, characterized by a low level of toxicityand a high therapeutic index, effective in small doses and with noundesirable side effects.

Another object of this invention is to create the neurotropic agentshaving the above pharmacological advantages with a simple, safe andinexpensive technological process.

Both of the aforementioned objects are solved by the invention bycreating new derivatives of the γ-aminobutyric acid:N-(4-hydroxy-3,3-dimethyl-2-oxo-1-butyryl)γ-aminobutyric acid (formulaI), ketopatoyl aminobutyrate. ##STR2## and its pharmaceuticallyacceptable salts.

The new compounds are characterized therein that they include amongtheir constituents, the keto(oxo)pantoic and the γ-aminobutyric acids,which together form an amide bond.

Unexpectedly, the new compounds have demonstrated a therapeutic indextwo orders higher than that of their analogue, pantogam and thetherapeutic index for the subject compounds is over 100. As well, thedesired effect was achieved at dosages a whole order lower than those ofpantogam. Furthermore, the synthesized compounds have exhibited a broadscope of activity in the central nervous system (sedative as well asanti-amnestic and antihypoxic effects were also observed).

The aforementioned properties are not only characteristic of theketopantoyl aminobutyrate compound, but also its various salts, inparticular, those of calcium and magnesium. Of all the salts derived,however, the best properties were demonstrated by the calcium salt ofthe synthesized acid.

The second object, that of improving the technological process forpreparing the drug of the invention, was solved by substitutingketopantolactone for one of the components in the synthesis, theD-pantolactone, used for producing pantogam. The production of thelatter excludes the separation of enantiomers, thereby improving thecost effectiveness of the entire product, rendering the technologicalprocess less harmful to the environment by decreasing the mount ofwaste, eliminating the need for great quantities of raw materials andsolvents, and decreasing power requirements.

The new compound, ketopantoic aminobutyrate, is obtained by condensationof the ketopantolactone in a mixture of a salt of the γ-aminobutyricacid and alcohol, and by subsequently treating the resultant productwith an organic or mineral acid or cation exchange resin hydrogen ionform.

The process, by which salts of ketopantoyl aminobutyrate are derived,excludes any treatment of the resultant product with either acid orsulfocationite.

The chemical structure of the ketopantoyl aminobutyrate and its saltshave been verified through element analysis and IR-spectra. Ketopantoylaminobutyrate is a colourless viscous liquid, readily soluble in waterand alcohol, but not in acetone or chloroform.

The calcium and magnesium salts of ketopantoyl aminobutyrate are in theform of whim hygroscopic powders, readily soluble in water and alcohol,but not in acetone or chloroform.

PREFERRED EMBODIMENTS OF THE INVENTION

Hereinafter, abbreviations will be used for the following terms:

KPA Ketopantoyl aminobutyrate

KPA-Ca calcium salt of ketopantoyl aminobutyrate

KPA-Mg magnesium salt of ketopantoyl aminobutyrate.

Examples 1-4 shall illustrate the preparation of the compounds of theinvention.

EXAMPLE 1

1.02 g (0.025 gram molecule) of metallic calcium is heated in 25 ml ofmethanol, for one hour, then 5.26 g (0.05 gram molecule) ofγ-aminobutyric acid are added and the mixture is stirred for one hour at65° C. 6.54g (0.05 gram molecule) of ketopantolactone are added and themixture is stirred for 1.5 hours at 65° C. Methanol is then distilled toa syrup-like residue and 50 ml of acetone is stirred in at roomtemperature. The product is then filtered, washed, through with acetone,then dried. 10.71 g of KPA-Ca is obtained. The yield is 85.6%. Themelting point is 208°-211° C. Found (in %): C 47.35; H 6.51: N 5.31: C₂₀H₃₂ O₁₀ N₂ Ca. Calculated for (in %): C 48.00; H 6.44; N 5.59.

IR spectrum: 3400 cm⁻⁴ (OH, NH); 1700 cm⁻¹ (ν₋₋ C=0); 1660 cm⁻¹ (ν₋₋ COamide I); 1560 cm⁻¹ (ν CN amide II).

EXAMPLE 2

1.43 g (0.025 gram molecule) of calcium oxide is added to 5.26 g (0.05gram molecule) of γ-aminobutyric acid in 25 ml of methanol. This mixtureis stirred for one hour at 65° C. 6.54 g (0.05 gram molecule) ofketopantolactone are added and stirred for one hour at 65° C. Themethanol is then distilled off, the residue is dissolved in 40 ml ofwater and extracted with chloroform. The acqueous layer is filteredthrough activated charcoal, evaporated and dried. 10.48 g of KPA-Ca isobtained. The yield is 83.8%. The melting point is 207°-210° C. (withdecomposition).

EXAMPLE 3

1.03 g (0.025 gram molecule) of magnesium oxide is added to 5.26 g (0.05gram molecule) of γ-aminobutyric acid in 25 ml of absolute ethylalcohol, and the mixture is stirred for 30 min. at 60° C. The reactionmixture is then filtered through a layer of activated charcoal. 6.54 g(0.05 gram molecule) of ketopantolactone are then added to the filtrateand stirred for one hour at 65° C. Next, the solution is evaporated andthe residue dried in a vacuum. 11.56 g (93.5%) of KPA-Mg is obtained.The melting point is 195°-198° C. (with decomposition).

EXAMPLE 4

10 g (0.02 gram molecule) of KPA-Ca, prepared as in Example 1, aredissolved in 50 ml of distilled water and passed through sulfocationite,in the form of H+. The cation exchange resin hydrogen ion form is thenrinsed with water until every trace of KPA has been eliminated from theeluate. The eluate is then concentrated, until it reaches a volume of 50ml, after which it is extracted with chloroform. The solution of KPA isthen evaporated, and the residue dried in a vacuum. 8.22 g (0.035 grammolecule) of KPA is obtained. The yield is 89%.

The central neurotropic activity of the new compounds was analyzed andtested by conventional methods, conducted in laboratory tests on whitecrossbred mice of both genders weighting 20±2 g. The spontaneous motoractivity (SMA) was measured in a 60 min. interval, with the 40-channelautomatic motor meter, according to the method described in the paper byJ. Knoll, Motormeter, a new sensitive apparatus for the quantitativemeasurement of hypermotility caused by phychostimulant, Arch. Internat.Pharmacodyn. Therap., 1961, No. 130, No. 1, pp. 141-154, in the revisionby K. S. Rayevsky and V. L. Timofeev, Multi-channel apparatus forregistering moto-activity of small laboratory animals, Bulletin (Newsrelease) of experimental biology, 1965, N 6, pp. 114-116. The method isbased on the principle of an electrical circuit, closed and opened bythe animals moving from one metal plate onto another. This test iscommonly used for testing sensitivity of the central nervous system(CNS) and the changes which occur under the influence of the substancebeing studied, resulting in either a depressing or stimulating activity.

In order to assess the ability of the new compounds to interfere withthe orientation reflexes (OR) of the animals, the latter were subjectedto the test of "ascent onto an inclined net" (Boissier J. R. Sinationlibre et psychotropes: Pharmacology of conditioning learning andretention, Proc. of 2nd International Pharmacological Meeting, London,N.Y., 1965, pp. 25-38). Suppressing of "exploratory" behaviour ofanimals is indicative of specific psychotropic properties of thesubstance, and, to a certain extent, characterizes its depressingeffect.

The myorelaxing effect of the new compounds was tested by the method ofthe "rotating rod"(Dunham N. W., Miga T. S., A note on a simplexapparatus for detecting neurological deficit in rat and mice, J. Am.Pharm. Ass., 1957, vol. 46, No. 3, pp. 208-209), which allows one torecord any abnormalities in coordination and balance, as well as ataxia.The mice in the laboratory tests were placed on a horizontal rod, 2 cmin diameter, rotating at a speed of 5 revolutions per minute. The objectwas to register the number of mice which were able to maintainequilibrium on the rod for two minutes. Any presence of a myorelaxingcomponent was considered to be a side effect of the substance beingstudied.

Determining the degree, to which a substance affects the duration ofsoporific activity produced by various barbiturates, is a conventionalmethod in experimental psychopharmacology, used for initialidentification of not only narcotic and soporific properties, but alsoof neuroleptic, tranquilizing, stimulating and other types ofpsychopharmacological activity, with one central active component.

Duration of the soporific activity of barbiturates (hexobarbital 100mg/kg, i.p.; barbital sodium 250 mg/kg, i.p.) was recorded from themoment the animals had lost the rotation reflex to the moment it wasrestored.

The chemical substance, in an acqueous solution, was injectedintraperitoneally, 60 min. before the start of the experiment. Anexception was made for tests involving barbiturates, in which case thesynthesized compound was injected 30 min. before the start of theexperiment. Its activity level was compared to that of pantogam,administered in "equi-molar" dosages. The acute toxicity was measured inmice, injected with the substance in the abdominal area. The averagelethal dose (LD₅₀) was calculated in accordance with theLitchfield-Wilcockson method.

The statistical analysis of the results of the experiments was cardedout on a computer using the "Turbo-dost5" and "Symphony-Probit"programs.

The acute toxicity analysis of KPA-Ca showed that the LD₁₀ of thiscompound used on mice, injected intraperitoneally, is equal to2234.3±60.7 mg/kg. Experiments conducted earlier with pantogam,administered under identical conditions, indicated the DL₅₀ of pantogamto be 2250 mg/kg. Therefore, the toxicity of both substances, whenadministered only once, is almost identical. However, the maximumtolerance level of pantogam is 1000 mg/kg, while that of KPA-Ca is 1500mg/kg.

When injected intravenously, the DL₅₀ of KPA-Ca is 1039.4±13.5 mg/kg,and that of pantogam is 1075 mg/kg.

The study of motor activity in the SMA test has shown that KPA-Cadecreases the motor activity in the test animals. The average number ofruns decreased considerably after the drug was administered, and thegreatest effect was observed with a dose of 150 mg/kg. Pantogam, wheninjected, also had a depressing effect on motor activity, however, thiseffect was evident only when much higher doses were administered. E.g.,The number of runs in the motor meter decreased by 30% after 500 mg/kgof pantogam were injected. The same result was achieved by injectingonly 10 mg/kg of KPA-Ca. That is 50 times less than the pantogam dose. A70% decrease in motor activity was produced by injecting 1000 mg/kg ofpantogam, the maximum tolerable dose. It took only 150 mg/kg (exactly 10times less than the maximum tolerable dose) of KPA-Ca to produce thesame effect. (Table 1)

                  TABLE 1                                                         ______________________________________                                        Effect of pantogam and KPA-Ca on spontaneous                                  motor activity in mice.                                                                Dose     Average     Relative change in                              Drug     (mg/kg)  SMA, M ± .sub.-- m                                                                     activity (%)                                    1        2        3           4                                               ______________________________________                                        Control group                                                                          --       632.8 ± 35.2                                                                           100                                             KPA-Ca    10      482.8 ± 101.8                                                                          76.3                                                      25      369.1 ± 68.7**                                                                         58.3                                                      50      338.9 ± 74.5**                                                                         53.6                                                     100      270.4 ± 75.3**                                                                         42.7                                                     150      190.6 ± 28.2***                                                                        30.1                                            Control group                                                                           0       524.0 ± 99.2                                                                           100                                             Pantogam 500      392.0 ± 307                                                                            74.8                                                     1000     176.0 ± 116*                                                                           33.6                                            ______________________________________                                         Note: Hereinafter, an asterix is used to indicate statistically verified      results:                                                                      *  where P < 0.05;                                                            **  where P < 0.01;                                                           ***  where P < 0.001.                                                    

The study of the effect the drugs have on the orientation reflexes ofthe animals, conducted in accordance with the "test of ascent onto aninclined net", have shown that KPA-Ca, when administered in dosagesbetween 0.1 and 150 mg/kg, does not disturb the "exploratory" behaviourof the animals. Pantogam, on the other hand, suppressed the orientationreflex in mice. The drug reaches its maximum strength 60 min. after ithas been administered. The average effective dose (DE₅₀) giving themaximum strength for pantogam is 680 (565-816) mg/kg.

Testing the effect KPA-Ca has on muscular strength and movementcoordination, according to the method of the "rotating rod", has shownthat the injection of the new substance in the same dosage range, didnot induce any ataxia, myorelaxation or loss of movement coordination inthe test animals during the entire test period (3.5 hours). At the sametime, administering pantogam in doses of 300 mg/kg and higher resultedin the loss of movement coordination, which was seen as a side effect ofthe drug. The maximum strength of the drug was demonstrated 30 min.after the pantogam was injected and movement coordination and musclestrength did not return until 1.5 hours after the start of theexperiment.

The analysis of the effect KPA-Ca has on the duration of the soporificaction of barbiturates revealed that the new compound considerablyprolongs the duration of sleep induced by barbiturates. In the case ofbarbital sodium, the effect of administering KPA-Ca in doses of 25, 50and 1130 mg/kg, surpassed the parameters taken from the control group by126.5, 95 and 129.3%. It should be noted that, at the same time, KPA-Cadecreases the amount of time it takes the animals to assume a lateralposition. Depending on the dose, the effect varies in the range from30.4 to 38.6 % of the control level. (Table 2).

                  TABLE 2                                                         ______________________________________                                        Effect of KPA-Ca on the soporific action of barbital sodium.                         Dose    Lateral position                                                                         %    Duration of sleep                              Drug   mg/kg   (min)      effect                                                                             (min)     % effect                             ______________________________________                                        Barbitol                                                                             250     38.1 ± 1.3                                                                            100  159.2 ± 11.2                                                                         100                                  sodium                                                                        KPA-Ca 1       26.5 ± 1.9***                                                                         69.6 159.1 ± 12.6                                                                         99.9                                        10      23.4 ± 1.5***                                                                         61.4 195.4 ± 12.1                                                                         122.7                                Barbitol                                                                             250     31.8 ± 1.1                                                                            100   53.5 ± 5.5                                                                          100                                  sodium                                                                        KPA-Ca 25      21.4 ± 0.6***                                                                         67.3 121.2 ± 12***                                                                        226.5                                Barbitol                                                                             250     34.5 ± 1.4                                                                            100   79.3 ± 8.1                                                                          100                                  sodium                                                                        KPA-Ca 50      23.7 ± 1.9**                                                                          68.7 154.7 ± 10.3***                                                                      195.1                                       100     23.0 ± 0.8***                                                                         66.7 181.8 ± 5.4***                                                                       229.3                                ______________________________________                                    

Similar results were obtained with the hexobarbital sleep mode. KPA-Ca,depending on the dosage administered, prolonged sleep duration in mice.The maximum effect was produced when injecting 100 mg/kg, at which timethe control group parameters were exceeded by 102.4%. As in the testwith barbital sodium, when the dose was increased to above 100 mg/kg,there was not noticeable change in the effect. In this model the KPA-Cahad no effect on the lateral position. This parameter fluctuated at±4.2% from the control group level. (Table 3).

                  TABLE 3                                                         ______________________________________                                        Effect of KPA-Ca on soporific action of hexobarbital.                                          Lateral        Duration                                               Dose    Position       of sleep                                      Drug     mg/kg   (min)    % effect                                                                            (min)    % effect                             ______________________________________                                        Hexobarbita                                                                            100     2.4 ± 0.15                                                                          100   46.3 ± 2.3                                                                          100                                  KPA-Ca    1      2.5 ± 0.17                                                                          104.2 44.6 ± 5.2                                                                          96.3                                           10     2.4 ± 0.16                                                                          100   67.2 ± 4.3**                                                                        145.1                                          25     2.5 ± 0.2                                                                           104.2 60.6 ± 1.9***                                                                       130.9                                          50     2.3 ± 0.15                                                                          95.8  70.7 ± 3.1***                                                                       152.7                                         100     2.4 ± 0.22                                                                          100   93.7 ± 4.3***                                                                       202.4                                         150     2.5 ± 0.34                                                                          104.2 86.4 ± 4***                                                                         186.6                                ______________________________________                                    

This test demonstrated that the new compounds are superior to pantogam.As indicated earlier, pantogam when administered in the therapeutic doseof 500 mg/kg increased by 20% the soporific effect of barbital sodium,and by 40% the effect of hexobarbital. The KPA-Ca, on the other hand, ata level 10 times lower (50 mg/kg), increased the duration of sleep by95.1% and 52.7%, respectively.

The antihypoxic properties of the new compounds were tested in themodels of hypoxic normobaric, hemic and histotoxic hypoxia. The hypoxic(hypercapnic) normobaric hypoxia was induced by placing the mice inhermetically sealed transparent boxes, subdivided into compartments, 80cm³ each. The animals were observed until all respiratory movementsceased. The hemic hypoxia was induced by the intraperitonealadministration of sodium nitrite in a dose of 400 mg/kg. The hystotoxichypoxia was induced by the intraperitoneal administration of sodiumnitroprussiate, in a dose of a 20 mg/kg dosage.

The analysis of antihypoxic properties of KPA-Ca in the variousexperimental models of hypoxia, demonstrated that, under the conditionsof normobaric hypoxia, the new compound, when administered in doses inthe range of 10 to 100 mg/kg, successfully extended the lifespan of thetest animals by 35.8-46% as compared to the control group. When used inthe model of histotoxic hypoxia, the KPA-Ca produced similiar results.However, any statistically significant increase in the lifespan ofanimals was registered at doses of 50 and 100 mg/kg Coy 21.6% and 38.4%,respectively). KPA-CA, under the conditions of the hemic hypoxia model,showed little activity. Only at 100 mg/kg, did its effect actuallyincrease by 19.9% (Table 4). It should be noted, that this test has notshown any considerable advantages of KPA-Ca over pantogam, with theexception of the fact that KPA-Ca produced results at significantlylower doses. E.g. pantogam, under the conditions of hystotoxic hypoxia,when administered in the following doses: 250, 500 and 1000 mg/kgincreased the lifespan of test animals by 57% and 85%, respectively.

                  TABLE 4                                                         ______________________________________                                        Effect of KPA-Ca on the lifespan of mice with induced hypoxia.                                     Average lifespan                                         Drug      Dose (mg/kg)                                                                             (sec)       % effect (M ± m)                          ______________________________________                                        Normobaric hypoxia                                                            Control group                                                                            0         411 ± 11.9                                                                             100                                          KPA-Ca    10         558 ± 21.5***                                                                          135.8                                                  25         570 ± 17.3***                                                                          138.7                                                  50         588 ± 22.4***                                                                          143.1                                                  100        600 ± 30.7***                                                                          146                                          Histotoxic hypoxia                                                            Na-nitro-prussiate                                                                      20         765 ± 38 100                                          KPA-Ca    10         798 ± 38 104.3                                                  25         855 ± 43.2                                                                             111.8                                                  50         930 ± 55.1*                                                                            121.6                                                  100        1059 ± 64**                                                                            138.4                                        Hemic hypoxia                                                                 Na-nitrite                                                                              400        790.5 ± 21.1                                                                           100                                          KPA-Ca    10         777 ± 30.1                                                                             98.3                                                   25         780 ± 30.3                                                                             98.7                                                   50         819 ± 41 103.6                                                  100        948 ± 40.3**                                                                           119.9                                        ______________________________________                                    

The effect produced by the new substance on the processes of the centralnervous system was examined on the model of one-time training of mice,of conditioned reaction of passive avoidance (CPRA), where the amnesiceffect was produced by electric shock. During the tests, a two-sectionchamber was used to condition a certain reflex to the lit and darkenedsections. First, for two minutes, the amount of time was registered,that a mouse spent in the lit section before entering the darkenedsection. Then, while in the darkened section, the animal would receive asingle electric shock through the electrode floor (training). Thetraining was immediately followed by an electric shock (50 Hz, 0.2 see).Memory was tested after 24 hours for 2 minutes. The substance wasintraperitoneally administered 40 min. prior to the start of thetraining, the control group received a physiological solution. Theamnesic effect of the electric shock was demonstrated insofar that, whenthe animal was tested 24 hours after developing CRPA, it showed no signsof fear of entering into the darkened "dangerous" section. Theanti-amnesic properties of the new compound are represented by anincrease in the latent period before and after the training. (Δt)

                  TABLE 5                                                         ______________________________________                                        The effect of KPA-Ca on the latent period of CRPA.                                       Latent period (sec)                                                         Dose               after         %                                   Drug     mg/kg   before training                                                                          training                                                                            t ± .sub.-- m, sec                                                                 effect                              ______________________________________                                        Control   0      34.1       31.1  -3 ± 6                                                                              91.2                               group +                                                                       amnesia                                                                       Control   0      29.4       84.7  55.3 ±                                                                             288.1                               group                             9.6***                                      w/o amnesia                                                                   KPA-Ca   10      27.1       90.3  63.2 ±                                                                             334.4                                                                 12.6**                                               25      31.4       102.4 71 ± 9***                                                                          396.1                                        50      30.6       77.8  47.2 ±                                                                             254.2                                                                 13.3**                                               100     31.8       82.8  51 ± 14.1**                                                                        260.4                               ______________________________________                                    

The study of the anti-amnesic properties of KPA-Ca in the CRPA modelillustrated that, in the control group of animals, application ofelectric shock had eradicated the acquired "skill" (taught by theelectric current passed through the electrode floor). The latent periodof time spent in the lit section of the chamber after 24 hours was91.2%. In the control group of animals, not exposed to the effect of theelectric shock, the latent period after the training had noticeablyincreased, by 288.1%. The administration of KPA-Ca had counteracted theamnesic effect of the electric shock and preserved the acquired"skills". This demonstrated the anti-amnesic properties of the testedsubstance (Table 5). Earlier tests of pantogam demonstrated that thisdrug, introduced in doses ranging from 250 to 500 mg/kg, has moderate aanti-amnesic effect, quantitatively representing 60-75% of the "model"latent period in animals not exposed to the electric shock.

INDUSTRIAL APPLICATION

Thus, results of the study of the pharmacological properties of the newcompounds, carried out in accordance with the methods ofneuropharmacological screening, have shown that the new compounds havethe following advantages, as compared with analogue substances:

1. sedative activity, as demonstrated in tests with barbiturates andSMA, is evident at doses lower by a whole point,

2. absence of the suppressant component in the sedative activity, asdemonstrated in the study of the orientation reflexes in the test of the"ascent on an inclined net",

3. absence of side effects, such as the myorelaxing activity, in theeffective dosage range,

4. higher effectiveness, in quantitative terms, as demonstrated in allthe tests of neuropharmacological screening,

5. broader therapeutic application of the new compound.

The new compounds have demonstrated sedative properties, and thecombination of their antihypoxic and anti-amnesic characteristics givesgrounds for considering KPA, as well as its salts, to be a nootropicdrug. KPA, at the same time, had no depressing effect on the animals,which leads us to believe that there are no side effects in the examineddosage range.

Results of the conducted study show the new compound to be a promisingneurotropic drug.

We claim:
 1. A compound of formula I: ##STR3## or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, which isthe calcium or magnesium salt of the compound of formula I.
 3. Acompound according to claim 2, which is the calcium salt of the compoundof formula I.
 4. Method for preparing a compound of formula I ##STR4##comprising condensing ketopantolactone with a salt of γ-aminobutyricacid, and thereafter treating the resultant salt product with an organicor mineral acid, or a cation exchange resin in hydrogen form.
 5. Methodfor preparing a salt of the compound of formula I ##STR5## comprisingcondensing ketopantolactone with a salt of γ-aminobutyric acid.
 6. Amethod according to claim 5, wherein the condensation is performed witha calcium salt of γ-aminobutyric acid in alcohol at a temperature of60°-65° C.